The rationale behind using these medications in modulating pain and gut function is that studies have evaluated the efficacy of both tricyclic antidepressants (TCAs) and SSRIs in IBS. The rationale behind their use is based on three theories. First, functional patients often have psychological comorbidities, particularly anxiety, somatization and depression. Second, these medications may have a modulating effect either through a centrally mediated action or a local gut action that changes visceral sensitivity and motor activity or both. Lastly, both SSRIs and TCAs seem to have a central effect in modulating pain.

Tricylics are well known for their pain-modulating effects. A recent metaanalysis assessed the efficacy of TCAs in the treatment of a variety of functional gastrointestinal disorders and found that the average number needed to treat was three. Recent studies further support the use of these medications in IBS. Drossman et al. evaluated the efficacy of the TCA desipramine in a 12-week, placebo-controlled study of patients with moderate to severe functional bowel disorders, although most met criteria for IBS. This medication (starting dose was 50 mg at bedtime) showed a statistically significant benefit over placebo in the per-protocol analysis, in which only the patients that completed treatment were included (73% versus 49%), but not in the intention-to-treat analysis. In clinical practice, tricyclic agents are often started at lower doses (e.g. 10 mg at bedtime) and gradually increased to the lowest, most effective dose to minimize side effects and increase tolerance. TCAs have been shown to improve symptoms particularly in IBS-D patients, presumably due to their anticholinergic effects.

The literature on SSRIs is even more limited but two recent studies evaluated the efficacy of paroxetine in IBS. In the first study, paroxetine was compared with psychotherapy and treatment as usual and was found to reduce health care costs, abdominal pain and health-related quality of life 3 months and 1 year later. A second study compared high-fiber diet alone or in conjunction with paroxetine or placebo. Overall, well being, which was measured by the Beck Depression Index and the IBS Quality of Life questionnaires, improved more with paroxetine compared with placebo (63% versus 26%). Anxiety also improved in the paroxetine group but bloating, pain and social functioning did not show improvement with the drug.

Other agents affecting both single and mixed receptor sites (similar to that of TCAs) are also being considered for the treatment of IBS. Combined reuptake inhibitors of both serotonin and norepinephrine, for example venlaxafine, may reduce colonic sensation and alter colonic tone. A newer similar agent, duloxetine, which was recently approved for the management of diabetic neuropathic pain, is also being considered for use in other chronic pain syndromes such as fibromyalgia and IBS.